The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). The resource comprised 906,359 women and men (66.9
Parastomal hernia (PSH) is a common complication after stoma creation and may present emergently with obstruction, incarceration, or ischemia. While minimally invasive surgery (MIS, laparoscopic or robotic) shows benefits in elective PSH repair, data in emergencies are limited. This study compared outcomes following open versus MIS emergent PSH repair. In this retrospective cohort using ACS-NSQIP, patients undergoing emergent open, laparoscopic, or robotic PSH repair were identified. Surgical approach was categorized as open or MIS. A 3:1 propensity score–matched analysis balanced demographic, comorbidity, physiologic, laboratory, and operative variables. Primary outcome was 30-day overall postoperative complications; secondary outcomes included wound, medical, and surgical complications, return to the operating room (OR), length of stay, and readmission. Multivariate logistic regression identified predictors of complications. Of 303 patients (249 open, 54 MIS), 192 were analyzed after matching (144 open, 48 MIS) with balanced baseline characteristics. MIS repair had lower overall complications than open repair (22.9
BACKGROUND:Capsule endoscopy (CE) is a valuable tool used in the diagnosis of small intestinal lesions. The study aims to systematically review the literature and provide a meta-analysis of the diagnostic accuracy, specificity, sensitivity, and negative and positive predictive values of AI-assisted CE in the diagnosis of small bowel lesions in comparison to CE. METHODS:Literature searches were performed through PubMed, SCOPUS, and EMBASE to identify studies eligible for inclusion. All publications up to 24 November 2024 were included. Original articles (including observational studies and randomized control trials), systematic reviews, meta-analyses, and case series reporting outcomes on AI-assisted CE in the diagnosis of small bowel lesions were included. The extracted data were pooled, and a meta-analysis was performed for the appropriate variables, considering the clinical and methodological heterogeneity among the included studies. Comprehensive Meta-Analysis v4.0 (Biostat Inc.) was used for the analysis of the data. RESULTS:A total of 14 studies were included in the present study. The mean age of participants across the studies was 54.3 years (SD 17.7), with 55.4% men and 44.6% women. The pooled accuracy for conventional CE was 0.966 (95% CI: 0.925-0.988), whereas for AI-assisted CE, it was 0.9185 (95% CI: 0.9138-0.9233). Conventional CE exhibited a pooled sensitivity of 0.860 (95% CI: 0.786-0.934) compared with AI-assisted CE at 0.9239 (95% CI: 0.8648-0.9870). The positive predictive value for conventional CE was 0.982 (95% CI: 0.976-0.987), whereas AI-assisted CE had a PPV of 0.8928 (95% CI: 0.7554-0.999). The pooled specificity for conventional CE was 0.998 (95% CI: 0.996-0.999) compared with 0.5367 (95% CI: 0.5244-0.5492) for AI-assisted CE. Negative predictive values were higher in AI-assisted CE at 0.9425 (95% CI: 0.9389-0.9462) versus 0.760 (95% CI: 0.577-0.943) for conventional CE. CONCLUSION:AI-assisted CE displays superior diagnostic accuracy, sensitivity, and positive predictive values albeit the lower pooled specificity in comparison with conventional CE. Its use would ensure accurate detection of small bowel lesions and further enhance their management.
Cellular senescence, a stress-induced program causing stable cell-cycle arrest, is a hallmark of liver aging, fibrosis, and cancer. However, the cell-type-specific mechanisms, spatial organization, and cancer-associated alterations in the liver remain unclear. We profiled 43 normal human livers spanning ages and fibrosis stages using a single-cell multiome, Xenium spatial transcriptomics, and CODEX, complemented by fibrotic mouse models and 24 colorectal cancer liver metastases. We found CDKN1A+ senescent hepatocytes, fibroblasts, cholangiocytes, and endothelial cells associated with age, liver disease, or cancer. Senescence differed between aged and fibrotic livers, with similar patterns in mice. Spatially, CDKN1A+ hepatocytes localized periportally, while SERPINE1+ aging-associated hepatocytes formed spatial clusters, potentially mediated by Claudins and THBS1. Fibrotic regions contained CXCL12+ senescent fibroblasts interacting with CXCR4+ immune cells. Chemotherapy intensified senescence in hepatocytes by 5-fold relative to aging and led to unique CDKN2A+ populations. Across conditions, senescent cells shared AP-1 activation, pro-inflammatory cytokines, and apoptosis resistance, suggesting therapeutic opportunities.
Dysregulated proteostasis and intracellular transport contribute to neurodegeneration. Histone deacetylase 6 (HDAC6), a therapeutic target of interest for neurodegenerative diseases, acts at a nexus modulating both proteostasis and intracellular transport. Inhibition of HDAC6 deacetylase activity promotes autophagic clearance of protein aggregates and increases α-tubulin acetylation, thereby enhancing microtubule resiliency and motor protein-microtubule binding, which facilitates intracellular transport and, subsequently, proteostasis. Despite these benefits, advancement of HDAC6 inhibitor therapeutics for neurodegenerative disease has been hindered by inadequate selectivity and CNS-penetrance of first-generation compounds. Here, we characterize a next-generation small molecule HDAC6 inhibitor, EKZ-438, in preclinical models of amyotrophic lateral sclerosis and frontotemporal dementia. We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8500-fold selectivity for HDAC6 versus all other HDAC6 paralogues), low nanomolar potency (12 nM) for HDAC6, and importantly, CNS-penetrance (unbound brain-to-plasma partition coefficient [Kp,uu,brain] ≥ 0.55) and high oral bioavailability (fraction of dose absorbed [F%] = 70). In complementary preclinical in vitro and in vivo immunolabelling and live imaging studies we tested the hypothesis that selective inhibition of HDAC6 deacetylase activity is sufficient to improve pathophysiological proteostasis and intracellular transport deficits in animal models of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease. EKZ-438 treatment rescued superoxide dismutase 1 (SOD1) (q < 0.0001) and transactive response DNA binding protein 43 kDa (TDP-43) (q < 0.001) proteostasis defects following an excitotoxic glutamate challenge, and increased survival of SOD1G93A and wild-type motor neurons by 59% (q < 0.0001) and 37% (q < 0.01), respectively, demonstrating in vitro neuroprotection. In SOD1G93A mice, EKZ-438 improved axonal transport by 16% (q < 0.05), motor performance by ∼40% (q < 0.05) and decreased plasma neurofilament light chain levels by 35% (q < 0.05), demonstrating in vivo neuroprotection. In a TDP-43 mouse model, EKZ-438 reduced TDP-43 pathology by ∼30% (q < 0.05) and neuroinflammation by ∼26% (q < 0.05) in the brain, supporting HDAC6 inhibition for sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Furthermore, EKZ-438 treatment improved intracellular transport by 39% (q < 0.001), rescued cytoplasmic TDP-43 accumulation by 87% (q < 0.0001) and restored nuclear TDP-43 splicing activity (P < 0.05) in human TARDBP neurons. These mechanistic improvements aligned with nearly complete rescue of human TARDBP and C9orf72 mutant neuron survival (P < 0.0001). We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal dementia.
